Pharmacologically-active trimethoxybenzoxyalkyl-piperazino(1&#39;)compounds

ABSTRACT

THE PRESENT INVENTION RELATES TO PHARMACOLOGICALLY-ACTIVE A-PIPERAZINOPHENYLACETONITRILE DERIVATIVES HAVING THE STRUCTURAL FORMULA   1-(((R4)M-PHENYL)-COO-A-),4-((R1,R2,R3-PHENYL)-CH(-CN)-)-   PIPERAZINE   WHEREIN R1, R2 AND R3 MAY BE HYDROGEN, HALOGEN OR ALKOXY GROUPS, WHERE R4 IS AN ALKOXY GROUP, WHERE MAY BE EITHER 1, 2 OR 3, AND WHERE A IS A STRAIGHT OR BRANCHED CHAIN ALKYLENE RADICAL CONTAINING 2-4 CARBON ATOMS, BY REACTING IN A CONVENTIONAL MANNER AN A-PIPERAZINOPHENYLACETONITRILE HAVING THE STRUCTURAL FORMULA   1-(HO-A-),4-((R1,R2,R3-PHENYL)-CH(-CN)-)PIPERAZINE   WITH AN ACID HALIDE OF AN ALKOXYBENZOIC ACID HAVING THE STRUCTURAL FORMULA   (HOOC-),(R4)M-BENZENE   AN ACID-BINDING AGENT BEING USED, IF DESIRED.

United States Patent 01 :"fice PHARMACOLOGICALLY-ACTIVE TRIMETHOXY-BENZOXYALKYL-PIPERAZINO [1'] COMPOUNDS Adolf Stachel, Frankfurt am Main,Fechenheim, Rudi Beyerle, Bruchkobel, and Rolf-Eberhard Nitz and KlausResag, Frankfurt am Main, Fechenheim, Germany, assignors to CasselaFarbwerke Mainkur Aktiengesellschaft, Frankfurt am Main, Germany NoDrawing. Filed Oct. 7, 1968, Ser. No. 765,692 Claims priority,application Germany, Oct. 12, 1967,

P 16 70 478.2 Int. Cl. C07d 51/70 US. Cl. 260-268CN 6 Claims ABSTRACT OFTHE DISCLOSURE The present invention relates to pharmacologically-activea-piperazinophenylacetonitrile derivatives having the structural formulaR ON wherein R R and R may be hydrogen, halogen or alkoxy groups, whereR, is an alkoxy group, where m may be either 1, 2 or 3, and where A is astraight or branched chain alkylene radical containing 2-4 carbon atoms,by reacting in a conventional manner an a-piperazinophenylacetonitrilehaving the structural formula R3 CN with an acid halide of analkoxybenzoic acid having the structural formula an acid-binding agentbeing used, if desired.

It has been discovered, in accordance with the present invention, thatcoronary dilators showing a positive inotropic eifect superior topreviously known coronary dilators can be produced by reacting, in thepresence of an acidbinding agent, if desired, anu-piperazinophenylacetonitrile having the structural formula where R Rand R is either hydrogen, halogen or alkoxy groups containing 1-4 carbonatoms; where A is a straight or branched chain alkylene radicalcontaining 2-4 carbon atoms, with an acid halide of an alkoxybenzoicacid having the structural formula HOOC- where R, is an alkoxy groupcontaining 1-4 carbon atoms, and where m may be either 1, 2 or 3.

The reaction may be carried out in any conventional manner butpreferably the reactants dissolved in an indifferent organic solvent areslowly mixed at room tempera- 3,594,384 Patented July 20, 1971 ture withstirring and then heated to reflux for several hours, preferably in thepresence of an acid-binding agent, such as sodium carbonate. Therecovered reaction products have the structural formula R CN 0111EXAMPLE 1 28 grams (0.1 mol) of a-(4'-fl-hydroxyethyl-piperazino[l]-4-chlorophenylacetonitrile were dissolved in 200 ml. of water-freebenzene containing 10.6 grams (0.1 mol) of sodium carbonate. To this wasthen added, drop by drop, at room temperature, while stirring, asolution of 23 grams (0.1 mol) of 3,4,5-trimethoxybenzoyl chloridedissolved in ml. of benzene. The resulting mixture was then refluxed for2 hours while stirring. After cooling, the reaction mixture was thenwashed repeatedly with water. After drying over calcium chloride,hydrogen chloride gas was passed into the solution until the latterbecame acid to Congo Red. In this manner the dihydrochloride of theu-(4'-B-3,4",5"-trimethoxybenzoxyethylpiperazino[l]-4-chlorphenylacetonitrilewas obtained in the form of colorless crystals which decomposed at C.Yield: 45 grams, i.e. 82.5% of the theoretical.

The a (4' B hydroxyethyl piperazino[1'] 4 chlorophenylacetonitrile usedas the starting material in this experiment was prepared as follows: 14grams (0.1 mol) of 4-chlorobenzaldehyde were added with stirring to 30grams of an ice-cooled solution of sodium bisulfite of 40%, by weight,concentration. After two hours there was added to this solution 13 grams(0.1 mol) of N-B-hydroxyethylpiperazine, care being taken to see thatthe temperature of the solution did not rise above about 30 C. When themixing was complete the temperature of the mixture was raised to 60 C.and a solution of 7.4 grams (0.15 mol) of sodium cyanide in 20 ml. ofwater added drop by drop. The resulting mixture was then stirredcontinuously for 4 hours and the reaction product recovered in ethylacetate. After drying over potassium carbonate the solution wasevaporated to dryness in vacuo. For further purification the product wasrecrystallized from benzine. The a-(4-fi-hydroxyethylpiperazino[l]-4-chlorophenylacetonitrile thus obtained melted at 98 C. Yield: 23grams, 82% of the theoretical.

In a manner analogous to the process described above, the intermediatescan be prepared having the general formula the values of R R R R R and Aand the melting points of the compounds thus produced being shown in thetable following.

R1, R2, R1 in position- 2 3 4 5 6 A M.P

H H 01 H H -CH2CH2OHz- 77 H H 01 H H CH2CH(OH;) 55-ss H H 1 H H-CH2CH2CH2CH2 57-59 H H oH3o H H --CHzCHz- 90 H CHaO CHaO H H CH2CH2CH2108 H CH3() CHaO H H CHzCH(CHa)- 1 161 H 01110 CHaO H H OHzCHzCHzCHg- 1204 oHio CHaO CHaO H H otnom- 98-100 CHsO CHaO CH3O H H -oH2oH2oHz 1 173C1130 C1130 01130 H H -oHloH(cH3)- 1 170 c1110 oHlo CHaO H HCHzCHzCHrCHz- 1 165 H CHsO CHaO CHaO H CH2CHz- 103 CHaO H H H c1110CHzCHz- 1 127 1 Dihydrochloride.

EXAMPLE 2 wherein the value of the various radicals is shown in the 42.2grams (0.1 mol) of a-(4'-/8-hydroxypropylpiperfollowing table:

R1, R2, R3 in position M P. of dihydro- 2 3 4 5 6 B4 A chloride H H 01 HH 3,4,5-0OH1 -CH2CH2CH2 143 H H 01 H H CHZCH(CH 112 H H Cl H H 148 H HCHaO H H H 158 H 01-130 (EH H H 141 H CHsO C1130 H H 105 H CHBO 01130 HH 157 CHaO CHaO CH3O H H 187 CHsO CHaO 01130 H H 131 (EH10 CHsO CHaO H HGHzCHzCHzCHz- 133 CHaO CHsO CIIJO II CH2 2* 180 C1130 H H H CHaO doCHgCHg- 90 CHsO CHQO (EH10 H H 3,4,5-0C2H5 GH2CH C H 148 1 Decomp.

azino[ l'] )2,3,4trimethoxyphenylacetonitrile were dissolved in 300 ml.of anhydrous chloroform containing 10.1 grams (0.1 mol) oftriethylamine. To this was then added drop by drop over a period of onehour, While stirring, 23 grams (0.1 mol) of 3,4,5-trimethoxybenzoy1chloride, dissolved in 100 m1. of anhydrous chloroform. After theexothermic reaction had subsided, the stirring was continued for aperiod of approximately two hours while maintaining the mixture at atemperature of 50 C. The resulting reaction mixture was then washed withwater, then with a 5%, by weight, aqueous solution of sodium bicarbonateand then again with water. After drying the washed solution overanhydrous sodium sulfate it was distilled in vacuo at 50 C. The residuethus obtained was dissolved in a small amount of ethyl acetate and tothe solution hydrogen chloride gas dissolved in ether added until thereaction of the solution became acid to Congo Red. The dihydrochlorideof the a-(4'-}3-3",4", 5" trimethoxybenzoxypropylpiperazino[1'])2,3,4-trimethoxyphenylacetonitrile thus obtained decomposed at 144 C.Yield: 50 grams-81% of the theoretical.

In a manner similar to those described above, compounds were preparedhaving the structural formula The a-piperazinophenylacetonitrilederivatives of the present invention, amongst other uses, have beenfound to be especially effective in the dilation of the coronary vesselsand have the added advantage of showing a positive inotropic effect,thus making them superior to other known coronary dilators. This utilityfor this purpose was determined by the procedures customarily used fordetermining the suitability of compounds as coronary dilators. That is,the dilation effect was determined on the basis of the change in oxygenpressure in the blood of the coronary veins of dogs, using the methodoutlined by W. K. A. Schaper et al. (cf. W. K. A. Schaper, R. Xhonneuxand J. M. Bogaard The Continuous Measurement of the Oxygen Pressure inthe Venous Coronary Blood, Naunyn-Schrniedebergs Arch. Exp. Path. u.Pharmak. 245, 383389 (1963). -In accordance with this method,anesthesized, spontaneously breathing dogs were given intravenousinjections of the test materials. Effective materials caused a dilationof the coronary arteries, thus producing an increase in the coronaryflow of the blood and causing an increase of the oxygen pressure in theblood of the coronary veins. Changes in the oxygen pressure weremeasured polarographically using a platinum electrode in accordance withthe method of Gleichmann-Luebbers (cf. 'U. Gleichmann and D. W.Luebbers, The Measurement of the Oxygen Pressure in Gases and LiquidsWith the Platinum Electrode With Special Consideration to the R3Measurement in Blood, Pfluegers Arch. 271, 431-455 Maximum change ofoxygen pressure in blood of coronary Maximum change Maximum change LD50,Dosage, veins of cardiac frequency of blood pressure gJkg. mg./ kg.Preparation mouse 1.v. Percent Mm. Percent Min. Percent Min.

a-(4-;3-3 ,4 ,5 trim ethoxybcnzoxyethyl-piperazine[1'])4-chlor-phenylacetonitrile 4. 0 +123 42 60 43 12 a-(4-fl-3 ,4 ,5trimjcthoxybenzoxypropyl-piperai.v.: 0. 2 +92 50 27 50 23 50zi110[1])-2,3,4-trimcthoxyphenylacetonitrile 0. 15 2. 0 +123 120 -23 12041 15 a-(4 18-3 ,4 ,5-trimethoxybenzoxyethyl-piperai.v.: 4. 0 +81 40 2250 47 20 zin0[1])4-methoxyphcnylacetonitrile 0. 11 a-(4-;3-3,4",5-trimethoxy-benzoxypropy1pipcra zino(1'])3-,4-dimethoxyphenylacetonitrile 0.5 +39 20 24 20 -23 20 a-( f'B-I,,4,5-t;rimethoxybenzoxyethyl-piperai.v.: 0. 5 +42 100 15 11 45 zino[1])-2,3,4trimethoxyphenylaoetonitrile- 0. 11 2.0 +102 +11 75 47 90a-(4'-'y-3' ,4,5"-trim1ethoxybenzoxypropyl-piperai.v.: 2.0 +96 50 19 3015 70 zinolll)-2,3,4-trimethoxyphcnylecetonitrile 0. 1a-(4'-B-3"-4"-5"-trimethoxy-benzoxyethyl-piperai.p.: 1 0 +77 20 +9 20 1910 zino[1]) -3,4,5-tr1m'ethoxyphenylacetonitrile 1. 1 a-(4-fi-3,4,5"-trimethoxybenzoxyethyl-piperazino[1])-2,6dimeth0xy-phcnylacetonitrile0. 5 +68 15 +4 15 13 15 (1960). The cardiac frequency was determinedcontinuously electronically from the systolic maximums of the arterialblood pressure. The arterial blood pressure was measured by conventionalmethods using a Statham-straingauge-electromanometer in the Arteriafemoralis.

The preceding table shows the results of tests made with a number of thewpiperazinophenylaeetonitrile derivatives described above, the testsbeing made on the dihydrochlorides of the stated compounds:

rne a-plperazlnopnenylacetonitrile derivatives of the present inventionare conveniently used in the form of coated or uncoated tabletscontaining measured amounts of the said derivative which may, ifdesired, be combined with other active ingredients as Well as with theusual tableting auxiliary agents such as starch, lactose, talcum powderand other known materials used in pill and tablet formation in thepharmaceutical industry. When used as injections, the hydrochloridederivatives of the ot-piperazinophenylacetonitrile are preferred sincethey are usually more soluble in water than certain of the otherderivatives. However, suitable injections can be prepared fromwater-insoluble derivatives of the a-piperazinophenylacetonitrile byemploying known suspension agents, emulsifiers and/or solubilizers inaccordance with procedures well known in the art.

What is claimed is:

1. a-Piperazinophenylacetonitrile compounds having the structuralformula R; N (Rn...

from straight and branched chain alkylene groups having 2-4 carbon atomsand m is selected from the integers 1, 2 and 3.

2. a-Piperazinophenylacetonitrile compounds according to claim 1 whereinthe said groups are selected to give the compounda-(4'-/3-3",4",5-trimethoxy-benzoxyethyl-piperazino[1'] )-4chlorphenylacetonitrile, and the dihydrochloride thereof.

3. wPiperazinophenylacetonitrile compounds according to claim 1 whereinthe said groups are selected to give the compound or (4'fl-3",4",5"-trimethoxy-benzoxypropyl-piperazino[1']) 2,3,4trimethoxy-phenylacetonitrile, and the dihydrochloride thereof.

4. a-Piperazinophenylacetonitrile compounds according to claim 1 whereinthe said groups are selected to give the compounda-(4'-fi-3",4",5"-trimethoxy-benzoxyethylpiperazino[l])-4-methoxyphenylacetonitrile,and the dihydrochloride thereof.

5. a-Piperazinophenylacetonitrile compounds according to claim 1 whereinthe said groups are selected to give the compound (45-3",4",5"-trimethoxy-benzoxyethylpiperazino[1])-2,3,4-trimethoxy-phenylacetonitrile, and the dihydrochloride thereof.

6. a-Piperazinophenylacetonitrile compounds according to claim 1 whereinthe said groups are selected to give the compound a.(4'7-3",4",5"-trimethoxy-benzoxypropylpiperazino 1'])-2,3,4-trimethoxy-phenylacetonitrile, and the dihydrochloride thereof.

References Cited UNITED STATES PATENTS 2,952,681 9/ 1960 Dodson 260-268DONALD G. DAUS, Primary Examiner U.S. Cl. X.R.

